A platform for research: civil engineering, architecture and urbanism
A platform for research: civil engineering, architecture and urbanism
Development of an organoid model for lung adenocarcinoma
Lung cancer is the leading cause of cancer-related death word-wide. To date, there is no approved targeted therapy for lung cancer driven by KRAS, the most frequently altered onco- gene in epithelial cancers. Despite the high incidence of KRAS-driven lung adenocarcinoma (LUAD), the underlying mechanisms that cause tumor progression are not well understood. Especially the early steps of tumorigenesis have not been studied extensively, as the research focus has been on advanced stage cancer. With early detection methods improving, it will be- come more important to understand the molecular changes directly following oncogenic KRAS expression, to develop targeted therapies particularly for KRAS-driven early-stage LUAD. New technologies, such as organoid cultures and single cell RNA-Sequencing, now facilitate the modeling and study of tumorigenesis in primary cells. For this reason, I developed an organoid system to faithfully model LUAD in vitro. I showed that transformed alveolar type 2 (AT2) cell-derived cancer organoids recapitulated LUAD pro- gression histologically. When transplanted orthotopically, the cancer organoids gave rise to tumors in vivo. I characterized the transcriptional landscape of oncogenic KRAS expressing cells early after transformation. Most notably, I found that oncogenic KRAS alone was suffi- cient to reprogram the cells to a more dedifferentiated phenotype, with reduced AT2 identity and increased expression of development genes. Using the transcriptional data, I identified and confirmed the ephrin receptor Epha2 as a potential target for early-stage LUAD. To further characterize the molecular changes that occur during tumor progression, I per- formed a time course analysis of the transcriptional landscape of alveolar organoids and cancer organoids with single cell resolution. I found that the alveolar organoids followed a regeneration response; the cells transitioned to alveolar type 1 (AT1) and AT2 cells in culture, similar to their differentiation trajectories in vivo. In contrast, ...
Development of an organoid model for lung adenocarcinoma
Lung cancer is the leading cause of cancer-related death word-wide. To date, there is no approved targeted therapy for lung cancer driven by KRAS, the most frequently altered onco- gene in epithelial cancers. Despite the high incidence of KRAS-driven lung adenocarcinoma (LUAD), the underlying mechanisms that cause tumor progression are not well understood. Especially the early steps of tumorigenesis have not been studied extensively, as the research focus has been on advanced stage cancer. With early detection methods improving, it will be- come more important to understand the molecular changes directly following oncogenic KRAS expression, to develop targeted therapies particularly for KRAS-driven early-stage LUAD. New technologies, such as organoid cultures and single cell RNA-Sequencing, now facilitate the modeling and study of tumorigenesis in primary cells. For this reason, I developed an organoid system to faithfully model LUAD in vitro. I showed that transformed alveolar type 2 (AT2) cell-derived cancer organoids recapitulated LUAD pro- gression histologically. When transplanted orthotopically, the cancer organoids gave rise to tumors in vivo. I characterized the transcriptional landscape of oncogenic KRAS expressing cells early after transformation. Most notably, I found that oncogenic KRAS alone was suffi- cient to reprogram the cells to a more dedifferentiated phenotype, with reduced AT2 identity and increased expression of development genes. Using the transcriptional data, I identified and confirmed the ephrin receptor Epha2 as a potential target for early-stage LUAD. To further characterize the molecular changes that occur during tumor progression, I per- formed a time course analysis of the transcriptional landscape of alveolar organoids and cancer organoids with single cell resolution. I found that the alveolar organoids followed a regeneration response; the cells transitioned to alveolar type 1 (AT1) and AT2 cells in culture, similar to their differentiation trajectories in vivo. In contrast, ...
Development of an organoid model for lung adenocarcinoma
Dost, Antonella (author) / Ehrmann, Michael
2024-03-18
Theses
Electronic Resource
English
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